OP0088 STRATIFIED MEDICINE: GENETIC PREDICTORS OF RADIOGRAPHIC OUTCOME IN RHEUMATOID ARTHRITIS
Authors: S. Sharma, N. Nair, J. Bowes, A. MacGregor, S. Verstappen, A. Barton, S. Viatte
Journal: Annals of the Rheumatic Diseases (2022)

Background Rheumatoid arthritis (RA) displays great heterogeneity between patients for susceptibility to developing erosions. Genetic variations within the HLA-DRB1 gene (the shared epitope (SE) and polymorphisms coding for Valine at position 11) have been consistently associated with both susceptibility and radiographic outcome in RA.(1) However, associations of non-HLA markers are much less conclusive. Most studies looking outside the HLA have been candidate gene studies and very few have been replicated in independent cohorts. Objectives: 1. Identify all single nucleotide polymorphisms (SNPs) outside the HLA that have ever been associated with radiographic outcome in RA 2. To perform a replication study to determine which of these are associated with radiographic outcome in the Norfolk Arthritis Register (NOAR), the worldwide largest prospective cohort with genetic and radiographic outcome data. Methods A systematic literature search was conducted as shown in the Figure 1. Figure 1. Flow chart for systematic review. The Norfolk Arthritis register (NOAR) is a large primary care-based inception cohort of patients diagnosed with inflammatory polyarthritis. Patients were recruited at baseline from 1989 and followed up prospectively for up to 20 years with serial X-rays. Genome-wide genotyping was performed on the Illumina Human/Infinium Core Exome array and imputed with Minimac4 to the Haplotype Reference Consortium panel. Quality control resulted in 7.5 million SNPs available in each patient. SNPs identified from the literature were extracted and tested for an association with the presence of erosions (as a longitudinal binary variable) using a generalized estimating equation (GEE) model in STATA/IC 14.0.in NOAR. Results A total of 2119 participants (2440 radiographs) were identified with both genetic and radiographic data available. 66.2% of these patients were female and 33.3% were anti-CCP positive. Median age of onset was 54.5 and 74.9% satisfied the American College of Rheumatology (ACR) 1987 criteria for rheumatoid arthritis. A total of 113 different non-HLA SNPs associated with radiographic outcome in RA were identified from the literature. Of these, 102 were successfully identified within NOAR and 91 were deemed to be independent SNPs based on R 2 of 0.6. 14 SNPs were found to be significantly associated with the presence of erosions within NOAR (Table 1). Table 1. SNPs found to be associated with radiographic severity within NOAR. *Significant results only; Dominant models used (Odds ratios displayed in relation to minor alleles) Gene Chromosome SNP (single nucleotide polymorphism Odds ratio (95% CI) P value IL2RB 2 rs743777 1.23 (1.01, 1.05) 0.0398 IL15 4 rs6821171 0.82 (0.67, 1.00) 0.0451 IL4 5 rs2243250 1.36 (1.08, 1.70) 0.0094 FOX03 6 rs12212067 0.75 (0.58, 0.97) 0.0278 OPG 8 rs2073618 0.79 (0.64, 0.98) 0.0295 TRAF1 9 rs10760130 1.33 (1.06, 1.65) 0.0118 TRAF1 9 rs10818488 1.32 (1.06, 1.64) 0.0141 TRAF1 9 rs2900180 1.32 (1.07, 1.61) 0.0079 IL4r 16 rs1805010 1.25 (1.01, 1.56) 0.0393 IL4r 16 rs1805011 1.31 (1.03, 1.66) 0.0260 LGALS9 17 rs3763959 1.28 (1.03, 1.59) 0.0260 SOST 17 rs4792909 1.34 (1.09, 1.65) 0.0052 LILRA3 19 rs103294 0.80 (0.65, 0.98) 0.0334 MMP9 20 rs11908352 0.70 (0.57, 0.85) 0.0005 Conclusion 113 non-HLA SNPs have been previously reported to be associated with radiographic outcome in RA. Of these, only ~15% also showed an association in NOAR, the largest cohort with genetic and radiographic outcome data worldwide. Interestingly, rs2243250, a SNP located on chromosome 5 (IL4), previously found to be associated in a small Egyptian cohort, has been replicated in NOAR.(2) Current work consists of assessing the added clinical value of a genetic risk score based on HLA and non-HLA markers in predicting radiographic outcome when combined with clinical/serological/demographic markers. References [1]S. Viatte et al. , JAMA 313 , 1645-1656 (2015). [2]Y. M. Hussein, A. S. El-Shal, N. A. Rezk, S. M. Abdel Galil, S. S. Alzahrani, Cytokine 61 , 849-855 (2013). Disclosure of Interests None declared.